No More Addictive Personality

use has such a long history in many cultures. According to George Koob, director of the US National Institute on Alcohol Abuse and Alco- holism in Bethesda, Maryland, the children of people who are dependent on alcohol are 3–5

times more likely to develop the disorder than NORDICPHOTOS/ALAMY the rest of the population — and this risk is roughly the same regardless of whether they are raised by their alcohol-dependent parents or adopted by parents who are not dependent on alcohol. The condition is about 60% heritable, he says, adding that this is “reasonably high”. Researchers may have managed to dem- onstrate that genetic predispositions exist, but linking particular genes or traits with addictions has proved much more difficult. Initial genetic findings are often announced with great fanfare, only to fail in replication or be found to have extremely small effects. “Addiction is very heterogeneous,” says Rutter, “There are many ways to get there.” DRUGS AND DISORDERS Some temperaments and disorders do raise the risk of addiction, however. About half of people with drug-use disorders have an additional psychiatric diagnosis, often a mood, anxiety or Genetics can influence addictive behaviour later in life, but linking genes to addiction is complicated. personality disorder. “What we’re finding is that the addictive personality, if you will, is multi- GENETICS faceted,” says Koob. “It doesn’t really exist as an entity of its own.” Some people with addictions have many personality traits, others have none, but only a few have all of them. No more addictive The personality disorder most commonly associated with addiction is antisocial personality disorder (ASPD), which involves dishonest, manipulative, insensitive and personality criminal behaviour. These characteristics make up the stereotype of someone with an addiction. “Antisocial behaviour and alcoholism and The role of temperament, metabolism and development drug abuse share a bunch of genetic risk factors,” make the inheritance of addiction a complex affair. says Kenneth Kendler, professor of psychiatry and human genetics at Virginia Commonwealth University in Richmond, who has studied these BY MAIA SZALAVITZ light on the causes of addiction — and it turns links in twins. “That’s replicated pretty robustly.” out that the idea of an addictive personality A large epidemiological study found that ne drunkard begets another, wrote is a myth. Instead, an enormous number of 18% of people with illegal-drug-use disorders the Greek philosopher Plutarch factors, ranging from early life trauma to genes have ASPD1, as do 9% of people with alcohol- nearly 2,000 years ago, demonstrating that code for metabolic enzymes, have a role use disorders2 — much higher than the 4% Othe age-old wisdom of the observation that in how the genetics of addiction unfold. By found in the general population. But although alcoholism runs in families. understanding how these factors fit together, having high levels of antisocial traits is one of But determining exactly what it is that researchers hope to develop strategies for the the best predictors of substance-use disorders, addicted parents pass down to their children prevention and treatment of addiction. most people with addictions do not have fully has proved difficult. Scientists have searched Plutarch was right to say that addiction is fledged ASPD, and most people with ASPD do for decades for an ‘addictive personality’ that often a familial trait — and it seems that much not have addictions. leaves someone vulnerable to drug prob- of this risk is carried genetically. Joni Rutter, Indeed, many people with substance depend- lems, but without success. Researchers have director of the Division of Basic Neuroscience ency do not have abnormal levels of antisocial tried to identify the genes responsible for and Behavioral Research at the US National traits at all. However, because breaking the law addiction, and they have examined the role of Institute on Drug Abuse in Bethesda, Mary- is itself a diagnostic symptom for antisocial early exposure to trauma. Yet they have failed land, says that regardless of the drug involved, behaviour, this trait will automatically be asso- to isolate a single genetic factor that reliably about 50% of the risk is genetic, within a range ciated with illegal drug addiction, even if the distinguishes between the 10–20% of people of about 40–60%. only laws that are violated are drug laws. who try alcohol or illegal drugs and get hooked Alcoholism is NATURE.COM Moreover, being extremely sensitive and and the majority who do not. the most widely A film on a new treatment overly cautious — essentially the opposite of Now, however, research into genetics and researched addic- for addiction is at: a callous, impulsive criminal — also raises the epigenetics is finally starting to shed some tion because alcohol go.nature.com/e1gqkk risk of addiction, although not by as much.

This suggests both that the stereotype of the cigarette addiction, CHRNA5, has essentially learning processes in humans that activate addictive personality badly mischaracterizes the opposite effect on smoking risk as ALDH2 similar circuitry, such as falling in love, so it is many people who have a substance-use disor- variant has for alcohol. Having just a single not clear whether this is unique to addiction. der, and that the genetic risk associated with variant can double the risk of nicotine addic- It is also not known whether these genes are ASPD does not account for most addictions. tion4. This link is one of the best supported in normally reactivated during adolescent brain Koob points out that addiction research, like any disease, not just in addiction, Rutter says. development, which might help to explain why the rest of psychiatry, is increasingly focus- Researchers initially thought that the adolescence and early adulthood is the highest- ing on the genetics that underlie symptoms, CHRNA5 variant, which codes for a subunit risk period for addictions. Because Rett syn- such as poor impulse control, rather than of the acetylcholine receptor that is affected by drome is profoundly disabling, those affected on syndromes such as alcoholism or ASPD. nicotine, would make nicotine more pleasura- are rarely exposed to drugs, so it is not known “There are specific types of symptoms that have ble. This would explain how the disorder affects addiction risk. underlying neurobiological bases,” he says. why people who smoke “Antisocial Kenny thinks that other genes linked to These temperamental or physiological and who have the vari- behaviour and developmental disorders may also be impor- predispositions can potentially develop into ant smoke more heav- alcoholism and tant in addictions — and not just in people many different disorders. For example, impul- ily than those without drug abuse who have these conditions, whose brains are sivity could lead to a range of problems: it is it. But instead, it sof- share a bunch wired differently from the start. If addiction a characteristic of addiction, ASPD, bipolar tens nicotine’s initial of genetic risk does reactivate brain-development genes, disorder, borderline personality disorder negative effects. Nearly factors.” more common variants could be involved. and many more. Impulsive behaviour also everyone who has ever “We should be looking for genes that cause increases the risk that teenagers will try drugs smoked reports that the first time is nauseating developmental disorders,” he says. — and make it harder for them to resist the at best. “When I tried cigarettes when I was a Another factor that affects both epigenet- urge when they want to stop. kid, I turned green and hated it,” says Rutter. ics and addiction risk is childhood trauma. By contrast, anxiety can drive addiction But people with the CHRNA5 variant have Severe stress in early life is known to dramati- in a different way: people who feel anxious a less unpleasant experience, says Paul Kenny, cally increase the risk of addiction, and the risk may take drugs to cope with social fears, and a pharmacologist at New York’s Mount Sinai increases with greater trauma exposure. For their difficulty stopping is not through a lack Hospital. “Instead of the drug being more example, a recent study of the entire Swedish of control, but because of a lack of alternative rewarding, what happened was that the population showed that people who as children ways to manage their emotions. This means aversive effects were diminished,” he says. either lost their parents, experienced a parent’s that programmes must be tailored to individ- Investigation of the CHRNA5 gene in knock- diagnosis of cancer, or witnessed domestic ual needs, not based on the idea that all people out mice showed that it is active in a brain region violence had twice the risk of a substance-use with addictions are the same. called the habenula, which is involved in avoid- disorder later in life compared with those who ance and aversion, even though it had not previ- did not have such stressful experiences6. PHYSIOLOGICAL FACTORS ously been strongly linked with addiction. The Indeed, some risk genes, such as those linked Personality is not the only way in which genes evidence also suggests that heavy smoking may to the serotonin transporter, may not cause can influence addiction risk. The strongest and damage the habenula by harming the neurons any problems unless there is a stressful early most replicated genetic risk factors for alcohol- that inhibit it. This would create strong negative environment. Both chronic stress and addic- ism involve genes linked to metabolism. These feelings and distress in those who smoke, which tion can induce some of the same epigenetic genes encode proteins that convert alcohol into they may try to fight with even more nicotine. changes in stress systems and in those involved acetaldehyde, and acetaldehyde into acetate. with pleasure, which may partly explain why Acetaldehyde is particularly toxic, and genes ADDICTION AND DEVELOPMENT addiction and trauma are so tightly linked. that cause it to build up in the blood, such as Epigenetic mechanisms, which control the “Early life experience may dictate whether or a variant of ALDH2, make even light drink- activity of genes by switching them on and off, not those genes or variations in those genes ing unpleasant. “When it is floating in their are also being seen as increasingly important in those different circumstances tend to come system, people don’t like it,” says Rutter. “They in addictions. Kenny’s lab studies these as well into play,” says Rutter. get really hot or feel nauseous.” Hangovers and found that one way that addiction can Given the increasing evidence of how varied and the anti-alcohol drug disulfiram produce epigenetically ‘rewire’ the brain is by turning addiction is, treatment and prevention pro- pretty much the same effect. on genes that are normally activated only dur- grammes will need to be significantly updated. Genes that lead to slow alcohol metabo- ing brain development. Some researchers are trying to work out how to lism are common in the Asian population. A For instance, a mutation in the MECP2 gene target prevention to particular temperaments, 2006 meta-analysis of 15 studies included is known to cause Rett syndrome, a develop- rather than attempt to reach both the anxious 4,500 Chinese, Japanese, Korean and Thai mental disorder found mainly in girls that and the impulsive with the same message. participants who were tested for genes related is associated with intellectual disability and “That’s the blessing and the curse,” says to the metabolism of acetaldehyde and acetate. autistic symptoms. During fetal and childhood Rutter. “There are many ways to get there, but The largest protective factor was the ALDH2 development, MECP2 regulates nerve-cell that also means many ways to intervene.” ■ variant, which makes people nine times less growth, and then it is silenced. However, when likely to develop alcoholism than those with rats are allowed to binge on cocaine, Mecp2 Maia Szalavitz is a science writer based in other variants of the gene3. expression “goes through the roof”, says Kenny. New York City. But even a gene that provides this much pro- Bingeing on cocaine rewires the brain, turning 1. Goldstein, R. B. et al. Drug Alcohol Depend. 90, tection can be overridden by environmental on genes that are usually quiescent in adults. 145–158 (2007). pressures. Between 1979 and 1992, for exam- Other animal experiments have shown that 2. Goldstein, R. B. et al. Alcohol. Clin. Exp. Res. 31, ple, the percentage of Japanese people who switching off the gene in the reward regions 814–828 (2007). 5 3. Luczak, S. E., Glatt, S. J. & Wall, T. J. Psychol. Bull. misused alcohol and who had this variant rose reduces cocaine intake . This suggests that the 132, 607–621 (2006). from 2.5% to 13%, as a heavy-drinking culture aberrant learning, which resists the negative 4. Fowler, C. D. & Kenny, P. J. Neuropharmacology 76, developed among businessmen that made it consequences of addiction, may be especially 533–544 (2014). 5. Im, H.-I. et al. Nature Neurosci. 13, 1120–1127 (2010). much harder to refuse to drink. deeply engrained. But the actions of MECP2 6. Giordano, G. N. et al. Addiction 109, 1119–1127 One gene that is strongly associated with have not been studied in normal emotional (2014).